title: Discovery of NMS-E973 as novel, selective and potent inhibitor of heat shock protein 90 (Hsp90).
abstract: Novel small molecule inhibitors of heat shock protein 90 (Hsp90) were discovered with the help of a fragment based drug discovery approach (FBDD) and subsequent optimization with a combination of structure guided design, parallel synthesis and application of medicinal chemistry principles. These efforts led to the identification of compound 18 (NMS-E973), which displayed significant efficacy in a human ovarian A2780 xenograft tumor model, with a mechanism of action confirmed in vivo by typical modulation of known Hsp90 client proteins, and with a favorable pharmacokinetic and safety profile.
authors.affiliation: Nerviano Medical Sciences S.r.l., Oncology, Viale Pasteur 10, 20014 Nerviano, MI, Italy. Electronic address: gabriella.brasca@nervianoms.com.
authors.forename: Maria Gabriella
authors.initials: MG
authors.lastname: Brasca
authors.forename: Sergio
authors.initials: S
authors.lastname: Mantegani
authors.forename: Nadia
authors.initials: N
authors.lastname: Amboldi
authors.forename: Simona
authors.initials: S
authors.lastname: Bindi
authors.forename: Dannica
authors.initials: D
authors.lastname: Caronni
authors.forename: Elena
authors.initials: E
authors.lastname: Casale
authors.forename: Walter
authors.initials: W
authors.lastname: Ceccarelli
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Colombo
authors.forename: Anna
authors.initials: A
authors.lastname: De Ponti
authors.forename: Daniele
authors.initials: D
authors.lastname: Donati
authors.forename: Antonella
authors.initials: A
authors.lastname: Ermoli
authors.forename: Gabriele
authors.initials: G
authors.lastname: Fachin
authors.forename: Eduard R
authors.initials: ER
authors.lastname: Felder
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Ferguson
authors.forename: Claudio
authors.initials: C
authors.lastname: Fiorelli
authors.forename: Marco
authors.initials: M
authors.lastname: Guanci
authors.forename: Antonella
authors.initials: A
authors.lastname: Isacchi
authors.forename: Enrico
authors.initials: E
authors.lastname: Pesenti
authors.forename: Paolo
authors.initials: P
authors.lastname: Polucci
authors.forename: Laura
authors.initials: L
authors.lastname: Riceputi
authors.forename: Francesco
authors.initials: F
authors.lastname: Sola
authors.forename: Carlo
authors.initials: C
authors.lastname: Visco
authors.forename: Fabio
authors.initials: F
authors.lastname: Zuccotto
authors.forename: Gianpaolo
authors.initials: G
authors.lastname: Fogliatto
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D001665:Binding Sites; D014408:Biomarkers, Tumor / Q000378:metabolism; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007555:Isoxazoles / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; C585926:NMS-E973
keywords: Anti-cancer agents; Fragment based drug discovery; Tumor cell proliferation inhibition